Demyelinating diseases of the central nervous system (CNS) are among the most devastating and disabling disorders that may arise during infancy through to adolescence and may lead to severe handicap and even death. A common feature of demyelinated lesions is the differentiation block of oligodendrocyte precursors (OPC) at a pre-myelinating stage. However, the mechanistic basis for inhibition of myelin repair is not fully understood. Our recent work together with others identified a Wnt/beta-catenin effector TCF7l2 as a new essential transcription factor for OPC differentiation. Activation of canonical Wnt signaling by stabilization of the -catenin/TCF complex was shown to inhibit oligodendrocyte differentiation. We further demonstrated that disruption of the -catenin/TCF7l2 interaction by HDAC1/2 reversed Wnt signaling inhibition and promoted oligodendrocyte differentiation, suggesting that TCF7l2 functions as a signaling integrator to control the timing of oligodendrocyte differentiation. The long-term objective of the research proposed here is to develop compounds that modulate the Wnt/TCF7l2 signaling to promote oligodendrocyte myelination and remyelination. We reason that surrogate targets for modulation of the Wnt/TCF7l2 activity might well be embedded within the TCF7l2 modifiers or downstream genetic targets. To understand the mechanism by which TCF7l2 controls oligodendrocyte differentiation and myelination in vivo, we will utilize floxed TCF7l2 mice that carry a cre-mediated conditional knockout mutation of TCF7l2 to examine the effect of loss of TCF7l2 on oligodendrocyte differentiation and TCF7l2 function at different developmental stages during oligodendrocyte development. In addition, we will use a combination of transcriptome-profiling and chromatin immunoprecipitation-sequencing approaches to identify TCF7l2 target genes on a genome-wide scale. These studies will provide new insights into the genetic program that TCF7l2 controls to mediate its effect on oligodendrocyte differentiation and myelination in the mammalian CNS. These studies will be crucial to our understating of the molecular basis of CNS myelination and suggest potential targets to Wnt/TCF signaling for treating patients with myelinating diseases such as multiple sclerosis and periventricular leukomalacia - a precursor lesion of cerebral palsy occurred in premature infants. PUBLIC HEALTH RELEVANCE: The work proposed in research plans will provide better understanding of CNS myelination and offer new therapeutic strategies to enhance myelin repair. It will not only have scientific merits but also could be of practical value in treating adult patients with myelinating disorders such as multiple sclerosis and periventricular cerebral palsy, the common cause of severe disability in infants.